Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive, inexorable loss of cognitive function (1). AD is the most common late-onset dementia, affecting several million people in the developed countries of the world. Approximately 4 million Americans suffer from Alzheimer's disease, at an annual cost of about $100 billion, making AD the third most costly disorder of aging. The disease is about twice as common in women as in men, and accounts for more than 65% of the dementias in the elderly. Early identification is critical in progressive conditions such as AD, because earlier treatment may be more effective than later treatment in preserving cognitive function. Furthermore, early detection may allow time to explore options for treatment and care. To date, however, a cure for Alzheimer's disease is not available, and cognitive decline is inevitable.
AD has two major neuropathological hallmarks: extracellular aggregates, called amyloid plaques, neuritic plaques, or senile plaques, which are composed of neurites, astrocytes, and glial cells around an amyloid core, and which are located in the cerebral cortex; and intracellular aggregates, called neurofibrillary tangles, which are composed of paired helical filaments). While senile plaques and neurofibrillary tangles occur with normal aging, they are much more prevalent in persons with Alzheimer's disease. Although the processes of AD could be triggered by many environmental insults, genetic studies have shown that mutations and polymorphisms of particular genes can confer susceptibility to this degenerative process.
Genetic studies of Alzheimer's disease patients have identified several early onset (<65 years old) disease risk factors (e.g., mutations in the amyloid precursor protein, Presenilin 1 and Presenilin 2), and a late-onset (>65 years old) disease risk factor, the E4 allele of apolipoprotein E (ApoE4) (see, e.g., U.S. Pat. Nos. 5,716,828; 5,767,248; and 6,136,530). In the late-onset AD (LOAD) population, only 50% of the subjects have been shown to carry the ApoE4 allele, which is compelling evidence to support the existence of additional genetic risk factors associated with AD. Indeed, recent linkage studies of LOAD-affected sibling pairs have identified loci on chromosomes 9 and 10 that may harbor risk-factor genes (2).
To date, the known risk factors for AD have been shown to modulate amyloid production or deposition; yet, none is necessary or sufficient for the diagnosis of AD, and none has demonstrated a role in the formation of neurofibrillary tangles (NFT). Extensive research on NFT has been undertaken in conjunction with studies on the conversion of tau, a protein that is normally soluble, into a hyperphosphorylated insoluble protein that is detected in NFT. Tau, a microtubule-associate protein is important in establishing and maintaining neuronal morphology. In addition to its role in normal cells, tau protein is involved in many neurodegenerative diseases, including AD, as the main component of intraneuronal aggregates. Some of the more common diseases with tau pathology include frontotemporal dementia (FTD), Pick's disease, and progressive supranuclear palsy (PSP) (3). The involvement of tau in these disorders has prompted much investigation into its function and role in the progression of these disorders.
Recently, several tau-coding mutations have been shown to segregate with FTD, and there have been some intriguing results with transgenic mice expressing the FTD-tau mutation, P301L, that develop tau aggregates (3, 4). However, in AD, no mutations have been found in the tau gene, suggesting that other factors are likely involved in the formation of tau aggregates. These factors could have implications for other neurodegenerative disorders with tau pathology (5-9).
In FTD and PSP subjects, recent genetic studies of the tau locus have shown that several mutations and a polymorphism segregate with these disorders, respectively (3). The identification and investigation of neighboring genes in the tau locus could be valuable in the study of molecular genetic risk factors in PSP, since there have been no reported tau coding or intronic mutations (10). This information could also be useful, not only for PSP, but for other neurodegenerative diseases, such as AD. The identification of new risk factors associated with AD and other neurodegenerative diseases may assist in the diagnosis of such diseases facilitate future preventive and therapeutic measures directed to these diseases.